SUMMARY/ABSTRACT HIV-associated neuropathic pain (HIV-NP) affects a significant proportion of people living with HIV (PLWH) and has a major impact on everyday functioning and quality of life in this population. Over the past decade a growing number of preclinical studies and clinical trials have indicated that cannabis administration and manipulation of the endocannabinoid (EC) system may have therapeutic utility in addressing HIV-NP. EC CB2 receptor activation and inhibition of the EC deactivation enzymes fatty acid amide hydrolase (FAAH) and monoacyglycerol lipase (MAGL) have been shown to decrease pain in rodent models of HIV-NP, while acute exposure to cannabis reduces self-reported pain in PLWH with neuropathy. However, little work has been conducted to elucidate the effects of the two primary cannabinoids (delta-9-tetrahydrocannabinol, THC and cannabidiol, CBD) on the EC system or to assess EC function in PLWH. The objective of this application is to address these fundamental gaps in our knowledge by: 1) examining the acute effect of administering NIDA- prepared THC/CBD products on HIV-NP; 2) utilizing mHealth text messaging to monitor daily real-world self- administered cannabis effects on pain; 3) assessing the relationship between cannabinoids and EC biomarkers, including ligands, enzymes, and receptor expression; and 4) conducting exploratory analyses to evaluate the effect of longitudinal cannabinoid use on changes in HIV-NP over time. We will examine the effect of low (0.20%), medium (1.3%), and high (13%) CBD-containing cannabis on NP, the EC system (ligands AEA and 2-AG, enzymes FAAH and MAGL, CB2 receptor expression), and heart rate variability (as a proposed objective biological measure of pain) in 120 PLWH who use cannabis to treat neuropathic pain. We will subsequently employ a mobile phone text messaging system, the Individual Monitoring of Pain And Cannabis Taken (IMPACT), to track cannabis exposure, CBD and THC consumption, and pain over a period of 6 months in these same PLWH participants. IMPACT will be used quantify the real-time effects of acute CBD/THC exposure on pain before and after cannabis self-administration, the real-time relationship between self- reported pain and changes in HRV, and to assess any longitudinal changes in NP, HIV clinical outcomes (viral load, CD4) and cognition during the 6-month period. This plan allows us to acquire data and compare the effects of cannabis product obtained from NIDA and self-administered cannabis obtained from local medicinal dispensaries. The overarching hypothesis is that CBD exposure and a higher CBD/THC ratio will exert beneficial effects both in the laboratory and during the observational study, including increasing EC biomarkers and reducing NP. In summary, this approach will advance our understanding about several key issues, including the interaction between cannabis constituents, the EC system and pain, the biological mechanisms that underlie these effects (EC enzymes, receptor), and the longer-term effects of cannabis use on health- related outcomes in HIV, including predictors of mortality (HRV, CD4, viral load) and neurocognition.